Class 1 and 11 gene products of the major histocompatibility complex (MHC) present foreign antigens to T-lymphocytes and are thus essential components of the immune response. These genes are also the most polymorphic loci known for vertebrates. It has generally been assumed that the maintenance of this unprecedented genetic diversity is due to the selective forces created by the diverse group of pathogens and parasites that are endemic to each species. However, the failure of one of the most critical predictions, that susceptibility to specific infectious diseases should correlate with certain MHC alleles, has created confusion. A wide variety of data indicate that these polymorphisms are maintained in natural populations by some form of strong balancing selection. Although many selective mechanisms have been postulated to contribute to the maintenance of these polymorphisms, little progress has been made towards identifying which mechanisms actually operate on MHC genes in natural populations. We propose to measure directly the selective mechanisms that maintain MHC diversity by analyzing fitness components in a captive wild mouse population. This population level approach allows the testing of hypotheses that could never be tested in the laboratory (e.g. frequency dependent hypotheses) and will directly answer the fundamental question of how MHC polymorphisms affect the fitness of individuals. The following fitness components will be examined. The influence of MHC genotypes on differential mortality and reproductive success will be measured. These data will allow testing of numerous disease based hypotheses such as heterozygote advantage and frequency dependent selection. Mating preferences within the enclosure will be determined through observations and paternity exclusion techniques (e.g. genetic fingerprinting). Mating preferences will also be tested in the laboratory, which will allow control of confounding variables inherent in natural social systems. Transmission distortion favoring MHC heterozygotes will be tested by checking informative laboratory matings for deviations from Mendelian expectations at birth. Population genetics models indicate that the maintenance of MHC polymorphisms requires relatively extreme levels of selection, operating either on survival or reproductive traits. Our ignorance concerning the mode of this selection is a major gap in our understanding of how pathogens and the vertebrate immune system interact.